tbuckley/cabot-search huggingface dataset:
A meta-analysis of immune-cell fractions at high resolution reveals novel associations with common phenotypes and health outcomes
Authors: Qi Luo, Varun B. Dwaraka, Qingwen Chen, Huige Tong, Tianyu Zhu, Kirsten Seale, Joseph M. Raffaele, Shijie C. Zheng, Tavis L. Mendez, Yulu Chen, Natalia Carreras, Sofina Begum, Kevin Mendez, Sarah Voisin, Nir Eynon, Jessica A. Lasky-Su, Ryan Smith, Andrew E. Teschendorff
Journal: Genome Medicine (2023)

Abstract Background Changes in cell-type composition of tissues are associated with a wide range of diseases and environmental risk factors and may be causally implicated in disease development and progression. However, these shifts in cell-type fractions are often of a low magnitude, or involve similar cell subtypes, making their reliable identification challenging. DNA methylation profiling in a tissue like blood is a promising approach to discover shifts in cell-type abundance, yet studies have only been performed at a relatively low cellular resolution and in isolation, limiting their power to detect shifts in tissue composition. Methods Here we derive a DNA methylation reference matrix for 12 immune-cell types in human blood and extensively validate it with flow-cytometric count data and in whole-genome bisulfite sequencing data of sorted cells. Using this reference matrix, we perform a directional Stouffer and fixed effects meta-analysis comprising 23,053 blood samples from 22 different cohorts, to comprehensively map associations between the 12 immune-cell fractions and common phenotypes. In a separate cohort of 4386 blood samples, we assess associations between immune-cell fractions and health outcomes. Results Our meta-analysis reveals many associations of cell-type fractions with age, sex, smoking and obesity, many of which we validate with single-cell RNA sequencing. We discover that naïve and regulatory T-cell subsets are higher in women compared to men, while the reverse is true for monocyte, natural killer, basophil, and eosinophil fractions. Decreased natural killer counts associated with smoking, obesity, and stress levels, while an increased count correlates with exercise and sleep. Analysis of health outcomes revealed that increased naïve CD4 + T-cell and N-cell fractions associated with a reduced risk of all-cause mortality independently of all major epidemiological risk factors and baseline co-morbidity. A machine learning predictor built only with immune-cell fractions achieved a C-index value for all-cause mortality of 0.69 (95%CI 0.67–0.72), which increased to 0.83 (0.80–0.86) upon inclusion of epidemiological risk factors and baseline co-morbidity. Conclusions This work contributes an extensively validated high-resolution DNAm reference matrix for blood, which is made freely available, and uses it to generate a comprehensive map of associations between immune-cell fractions and common phenotypes, including health outcomes.
Issue Information
Journal: Allergy (2023)

Through the eyes of children About the cover Atopic Derma sThe prevalence of atopic derma s has been on the rise, becoming a signifi cant global health concern.This chronic infl ammatory skin disorder aff ects individuals of all ages, with substan al impacts on their quality of life and general health care burden.Recognizing the mul factorial nature of atopic derma s becomes crucial in devising successful preven on methods and advancing therapeu c interven ons.
An electrogenetic interface to program mammalian gene expression by direct current
Authors: Jinbo Huang, Shuai Xue, Peter Buchmann, Ana Palma Teixeira, Martin Fussenegger
Journal: Nature Metabolism (2023)

Wearable electronic devices are playing a rapidly expanding role in the acquisition of individuals' health data for personalized medical interventions; however, wearables cannot yet directly program gene-based therapies because of the lack of a direct electrogenetic interface. Here we provide the missing link by developing an electrogenetic interface that we call direct current (DC)-actuated regulation technology (DART), which enables electrode-mediated, time- and voltage-dependent transgene expression in human cells using DC from batteries. DART utilizes a DC supply to generate non-toxic levels of reactive oxygen species that act via a biosensor to reversibly fine-tune synthetic promoters. In a proof-of-concept study in a type 1 diabetic male mouse model, a once-daily transdermal stimulation of subcutaneously implanted microencapsulated engineered human cells by energized acupuncture needles (4.5 V DC for 10 s) stimulated insulin release and restored normoglycemia. We believe this technology will enable wearable electronic devices to directly program metabolic interventions.
A gender specific risk assessment of coronary heart disease based on physical examination data
Authors: Hui Yang, Ya-Mei Luo, Cai-Yi Ma, Tian-Yu Zhang, Tao Zhou, Xiao-Lei Ren, Xiao-Lin He, Ke-Jun Deng, Dan Yan, Hua Tang, Hao Lin
Journal: npj Digital Medicine (2023)

Large-scale screening for the risk of coronary heart disease (CHD) is crucial for its prevention and management. Physical examination data has the advantages of wide coverage, large capacity, and easy collection. Therefore, here we report a gender-specific cascading system for risk assessment of CHD based on physical examination data. The dataset consists of 39,538 CHD patients and 640,465 healthy individuals from the Luzhou Health Commission in Sichuan, China. Fifty physical examination characteristics were considered, and after feature screening, ten risk factors were identified. To facilitate large-scale CHD risk screening, a CHD risk model was developed using a fully connected network (FCN). For males, the model achieves AUCs of 0.8671 and 0.8659, respectively on the independent test set and the external validation set. For females, the AUCs of the model are 0.8991 and 0.9006, respectively on the independent test set and the external validation set. Furthermore, to enhance the convenience and flexibility of the model in clinical and real-life scenarios, we established a CHD risk scorecard base on logistic regression (LR). The results show that, for both males and females, the AUCs of the scorecard on the independent test set and the external verification set are only slightly lower (<0.05) than those of the corresponding prediction model, indicating that the scorecard construction does not result in a significant loss of information. To promote CHD personal lifestyle management, an online CHD risk assessment system has been established, which can be freely accessed at http://lin-group.cn/server/CHD/index.html .
Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial
Authors: Manish A. Shah, Kohei Shitara, Jaffer A. Ajani, Yung-Jue Bang, Peter Enzinger, David Ilson, Florian Lordick, Eric Van Cutsem, Javier Gallego Plazas, Jing Huang, Lin Shen, Sang Cheul Oh, Patrapim Sunpaweravong, Hwoei Fen Soo Hoo, Haci Mehmet Turk, Mok Oh, Jung Wook Park, Diarmuid Moran, Pranob Bhattacharya, Ahsan Arozullah, Rui-Hua Xu
Journal: Nature Medicine (2023)

There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .
Personalized 3D‐Printed Scaffolds with Multiple Bioactivities for Bioroot Regeneration
Authors: Yibing Huang, Zhijun Zhang, Fei Bi, Huilin Tang, Jiahao Chen, Fangjun Huo, Jie Chen, Tingting Lan, Xiangchen Qiao, Xiutian Sima, Weihua Guo
Journal: Advanced Healthcare Materials (2023)

Recent advances in 3D printing offer a prospective avenue for producing transplantable human tissues with complex geometries; however, the appropriate 3D-printed scaffolds possessing the biological compatibility for tooth regeneration remain unidentified. This study proposes a personalized scaffold of multiple bioactivities, including induction of stem cell proliferation and differentiation, biomimetic mineralization, and angiogenesis. A brand-new bioink system comprising a biocompatible and biodegradable polymer is developed and reinforced with extracellular matrix generated from dentin tissue (treated dentin matrix, TDM). Adding TDM optimizes physical properties including microstructure, hydrophilicity, and mechanical strength of the scaffolds. Proteomics analysis reveals that the released proteins of the 3D-printed TDM scaffolds relate to multiple biological processes and interact closely with each other. Additionally, 3D-printed TDM scaffolds establish a favorable microenvironment for cell attachment, proliferation, and differentiation in vitro. The 3D-printed TDM scaffolds are proangiogenic and facilitate whole-thickness vascularization of the graft in a subcutaneous model. Notably, the personalized TDM scaffold combined with dental follicle cells mimics the anatomy and physiology of the native tooth root three months after in situ transplantation in beagles. The remarkable in vitro and in vivo outcomes suggest that the 3D-printed TDM scaffolds have multiple bioactivities and immense clinical potential for tooth-loss therapy.
Rational design of a booster vaccine against COVID-19 based on antigenic distance
Authors: Ye-Fan Hu, Terrence Tsz-Tai Yuen, Hua-Rui Gong, Bingjie Hu, Jing-Chu Hu, Xuan-Sheng Lin, Li Rong, Coco Luyao Zhou, Lin-Lei Chen, Xiaolei Wang, Chaobi Lei, Thomas Yau, Ivan Fan-Ngai Hung, Kelvin Kai-Wang To, Kwok-Yung Yuen, Bao-Zhong Zhang, Hin Chu, Jian-Dong Huang
Journal: Cell Host & Microbe (2023)

Current COVID-19 vaccines are highly effective against symptomatic disease, but repeated booster doses using vaccines based on the ancestral strain offer limited additional protection against SARS-CoV-2 variants of concern (VOCs). To address this, we used antigenic distance to in silico select optimized booster vaccine seed strains effective against both current and future VOCs. Our model suggests that a SARS-CoV-1-based booster vaccine has the potential to cover a broader range of VOCs. Candidate vaccines including the spike protein from ancestral SARS-CoV-2, Delta, Omicron (BA.1), SARS-CoV-1, or MERS-CoV were experimentally evaluated in mice following two doses of the BNT162b2 vaccine. The SARS-CoV-1-based booster vaccine outperformed other candidates in terms of neutralizing antibody breadth and duration, as well as protective activity against Omicron (BA.2) challenge. This study suggests a unique strategy for selecting booster vaccines based on antigenic distance, which may be useful in designing future booster vaccines as new SARS-CoV-2 variants emerge.
Stress induces behavioral abnormalities by increasing expression of phagocytic receptor MERTK in astrocytes to promote synapse phagocytosis
Authors: Youkyeong Gloria Byun, Nam-Shik Kim, Gyuri Kim, Yi-Seon Jeon, Jong Bin Choi, Chan-Woo Park, Kyungdeok Kim, Hyunsoo Jang, Jinkyeong Kim, Eunjoon Kim, Yong-Mahn Han, Ki-Jun Yoon, Seung-Hee Lee, Won-Suk Chung
Journal: Immunity (2023)

Childhood neglect and/or abuse can induce mental health conditions with unknown mechanisms. Here, we identified stress hormones as strong inducers of astrocyte-mediated synapse phagocytosis. Using in vitro, in vivo, and human brain organoid experiments, we showed that stress hormones increased the expression of the Mertk phagocytic receptor in astrocytes through glucocorticoid receptor (GR). In post-natal mice, exposure to early social deprivation (ESD) specifically activated the GR-MERTK pathway in astrocytes, but not in microglia. The excitatory post-synaptic density in cortical regions was reduced in ESD mice, and there was an increase in the astrocytic engulfment of these synapses. The loss of excitatory synapses, abnormal neuronal network activities, and behavioral abnormalities in ESD mice were largely prevented by ablating GR or MERTK in astrocytes. Our work reveals the critical roles of astrocytic GR-MERTK activation in evoking stress-induced abnormal behaviors in mice, suggesting GR-MERTK signaling as a therapeutic target for stress-induced mental health conditions.
Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting
Authors: Alba Capelo-Diz, Sofía Lachiondo-Ortega, David Fernández-Ramos, Jorge Cañas-Martín, Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, Maria J. González-Rellan, Laura Mosca, Joan Blazquez-Vicens, Alberto Tinahones-Ruano, Marcos F. Fondevila, Mason Buyan, Teresa C. Delgado, Virginia Gutierrez de Juan, Paula Ayuso-García, Alejandro Sánchez-Rueda, Sergio Velasco-Avilés, Héctor Fernández-Susavila, Cristina Riobello-Suárez, Bartlomiej Dziechciarz, Cristina Montiel-Duarte, Fernando Lopitz-Otsoa, Maider Bizkarguenaga, Jon Bilbao-García, Ganeko Bernardo-Seisdedos, Ana Senra, Mario Soriano-Navarro, Oscar Millet, Ángel Díaz-Lagares, Ana B. Crujeiras, Aida Bao-Caamano, Diana Cabrera, Sebastiaan van Liempd, Miguel Tamayo-Caro, Luigi Borzacchiello, Beatriz Gomez-Santos, Xabier Buqué, Diego Sáenz de Urturi, Francisco González-Romero, Jorge Simon, Rubén Rodríguez-Agudo, Asier Ruiz, Carlos Matute, Daniel Beiroa, Juan M. Falcon-Perez, Patricia Aspichueta, Juan Rodríguez-Cuesta, Marina Porcelli, María A. Pajares, Cristina Ameneiro, Miguel Fidalgo, Ana M. Aransay, Tomas Lama-Díaz, Miguel G. Blanco, Miguel López, Ricardo Villa-Bellosta, Timo D. Müller, Rubén Nogueiras, Ashwin Woodhoo, María Luz Martínez-Chantar, Marta Varela-Rey
Journal: Cell Metabolism (2023)

There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive β-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.
A non-human primate derived anti-P-selectin glycoprotein ligand-1 antibody curtails acute pancreatitis by alleviating the inflammatory responses
Authors: Yuhan Li, Xiangqing Ding, Xianxian Wu, Longfei Ding, Yuhui Yang, Xiaoliang Jiang, Xing Liu, Xu Zhang, Jianrong Su, Jianqing Xu, Zhiwei Yang
Journal: Acta Pharmaceutica Sinica B (2023)

Acute pancreatitis (AP) is a devastating disease characterized by an inflammatory disorder of the pancreas. P-selectin glycoprotein ligand-1 (PSGL-1) plays a crucial role in the initial steps of the adhesive at process to inflammatory sites, blockade of PSGL-1 might confer potent anti-inflammatory effects. In this study, we generated two non-human primate derived monoclonal antibodies capable of efficiently targeting human PSGL-1, RH001-6 and RH001-22, which were screened from immunized rhesus macaques. We found that RH001-6, can effectively block the binding of P-selectin to PSGL-1, and abolish the adhesion of leukocytes to endothelial cells in vitro. In vivo, we verified that RH001-6 relieved inflammatory responses and pancreatic injury in both caerulein and l-arginine induced AP models. We also evaluated the safety profile after RH001-6 treatment in mice, and verified that RH001-6 did not cause any significant pathological damages in vivo. Taken together, we developed a novel non-human primate derived PSGL-1 blocking antibody with high-specificity, named RH001-6, which can interrupt the binding of PSGL-1 and P-selectin and attenuate inflammatory responses during AP. Therefore, RH001-6 is highly potential to be further developed into therapeutics against acute inflammatory diseases, such as AP.
Mechanosensitive Piezo1 channel in physiology and pathophysiology of the central nervous system
Authors: Boyi Zong, Fengzhi Yu, Xiaoyou Zhang, Yige Pang, Wenrui Zhao, Peng Sun, Lin Li
Journal: Ageing Research Reviews (2023)

Since the discovery of the mechanosensitive Piezo1 channel in 2010, there has been a significant amount of research conducted to explore its regulatory role in the physiology and pathology of various organ systems. Recently, a growing body of compelling evidence has emerged linking the activity of the mechanosensitive Piezo1 channel to health and disease of the central nervous system. However, the exact mechanisms underlying these associations remain inadequately comprehended. This review systematically summarizes the current research on the mechanosensitive Piezo1 channel and its implications for central nervous system mechanobiology, retrospects the results demonstrating the regulatory role of the mechanosensitive Piezo1 channel on various cell types within the central nervous system, including neural stem cells, neurons, oligodendrocytes, microglia, astrocytes, and brain endothelial cells. Furthermore, the review discusses the current understanding of the involvement of the Piezo1 channel in central nervous system disorders, such as Alzheimer's disease, multiple sclerosis, glaucoma, stroke, and glioma.
Human herpesvirus-6 reactivation and disease after allogeneic haematopoietic cell transplantation in the era of letermovir for cytomegalovirus prophylaxis
Authors: Eleftheria Kampouri, Danniel Zamora, Erika S. Kiem, Winnie Liu, Sarah Ibrahimi, Rachel L. Blazevic, Erika A. Lovas, Louise E. Kimball, Meei-Li Huang, Keith R. Jerome, Masumi Ueda Oshima, Marco Mielcarek, Danielle M. Zerr, Michael J. Boeckh, Elizabeth M. Krantz, Joshua A. Hill
Journal: Clinical Microbiology and Infection (2023)
JAK inhibition ameliorated experimental autoimmune encephalomyelitis by blocking GM-CSF-driven inflammatory signature of monocytes
Authors: Shuai Shao, Chengjuan Chen, Gaona Shi, Yu Zhou, Yazi Wei, Lei Wu, Lan Sun, Tiantai Zhang
Journal: Acta Pharmaceutica Sinica B (2023)

Monocytes are key effectors in autoimmunity-related diseases in the central nervous system (CNS) due to the critical roles of these cells in the production of proinflammatory cytokines, differentiation of T-helper (Th) cells, and antigen presentation. The JAK-STAT signaling is crucial for initiating monocytes induced immune responses by relaying cytokines signaling. However, the role of this pathway in modulating the communication between monocytes and Th cells in the pathogenesis of multiple sclerosis (MS) is unclear. Here, we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory monocytes in experimental autoimmune encephalomyelitis (EAE), a model for MS. JAK inhibition prevented the CNS-infiltrating CCR2-dependent Ly6Chi monocytes and monocyte-derived dendritic cells in EAE mice. In parallel, the proportion of GM-CSF+CD4+ T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition, which in turns converted CNS-invading monocytes into antigen-presenting cells to mediate tissue damage. Together, our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of monocytes.
A tumor microenvironment-activatable nanoplatform with phycocyanin-assisted in-situ nanoagent generation for synergistic treatment of colorectal cancer
Authors: Xiaoxiao Sun, Xiaoye Liang, YuKai Wang, Pengcheng Ma, Weiwei Xiong, Shiyu Qian, Yu Cui, Haiyang Zhang, Xiang Chen, Fang Tian, Yang Shi, Fenfen Zheng, Lingling Li
Journal: Biomaterials (2023)
Micromolded honeycomb scaffold design to support the generation of a bilayered RPE and photoreceptor cell construct
Authors: In-Kyu Lee, Ruosen Xie, Agustin Luz-Madrigal, Seunghwan Min, Jingcheng Zhu, Jiahe Jin, Kimberly L. Edwards, M. Joseph Phillips, Allison L. Ludwig, David M. Gamm, Shaoqin Gong, Zhenqiang Ma
Journal: Bioactive Materials (2023)

Age-related macular degeneration (AMD) causes blindness due to loss of retinal pigment epithelium (RPE) and photoreceptors (PRs), which comprise the two outermost layers of the retina. Given the small size of the macula and the importance of direct contact between RPE and PRs, the use of scaffolds for targeted reconstruction of the outer retina in later stage AMD and other macular dystrophies is particularly attractive. We developed microfabricated, honeycomb-patterned, biodegradable poly(glycerol sebacate) (PGS) scaffolds to deliver organized, adjacent layers of RPE and PRs to the subretinal space. Furthermore, an optimized process was developed to photocure PGS, shortening scaffold production time from days to minutes. The resulting scaffolds robustly supported the seeding of human pluripotent stem cell-derived RPE and PRs, either separately or as a dual cell-layered construct. These advanced, economical, and versatile scaffolds can accelerate retinal cell transplantation efforts and benefit patients with AMD and other retinal degenerative diseases.